Abstract

Beta-thalassemia is a hereditary blood disorder characterized by reduced or absent synthesis of the beta-globin chain, one of the major components of adult hemoglobin (Hb). The unbalanced synthesis of globin chains leads to a relative excess of alpha-globin and heme, resulting in hemichrome-induced cellular damage in bone marrow erythroblasts and circulating erythrocytes. This, in turn, contributes to ineffective erythropoiesis, hemolysis and reduced red blood cell (RBC) survival, hallmarks of beta-thalassemia. We have previously reported that reduction in cellular heme synthesis by bitopertin, an oral, reversible, potent and selective glycine transporter 1 (GlyT1) inhibitor, positively impacts the disease pathology in a beta-thalassemia mouse model. It was hypothesized that reduced heme synthesis down-regulates globin production and as such diminishes the alpha-chain excess, driving the observed improvements in Hb, hemolysis and RBC survival in beta-thalassemia mice.

In study BP39642 (NCT03271541), a multicenter, single arm, proof-of-mechanism study, we investigated the safety, tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple oral doses of bitopertin in adult patients with non-transfusion-dependent (NTD) beta-thalassemia. Participants underwent a 6-week dose-escalation period followed by up to 10 weeks of treatment at the attained target dose. Tolerability was acceptable in NTD beta-thalassemia patients. Adverse events observed were in line with expectations from previous trials, with transient but repetitive headache and dizziness being the most prominent events. The PK characteristics of bitopertin were consistent with healthy volunteers and non-thalassemic patients. PD data from 8 patients treated for 8 week showed that Hb levels, the primary efficacy outcome measure in this study, decreased from a mean value of 8.5 g/dL at baseline to 8.1 g/dL at week 9 (-5.2%). The mean corpuscular hemoglobin (MCH) content of erythrocytes and reticulocytes decreased by 2 pg (-9.3%) and 1.8 pg (-7.8%), respectively. Absolute counts of reticulocytes remained largely unchanged over the treatment period (+1.4%), while the total number of circulating RBCs increased from 4.3 x10E12/L to 4.5 x10E12/L (+6%).

Based on these results, we concluded that treatment with bitopertin in NTD beta-thalassemia patients results in an expected inhibition of heme biosynthesis. Contrary to the observations in beta-thalassemia mice this did not lead to an improved disease phenotype in patients. We postulate that the negative effects of bitopertin on Hb synthesis were not sufficiently compensated by the observed increase in RBC count. We will present and discuss data that led to an early termination of the study and the implications for future research in this field.

Disclosures

Taher:Ionis Pharmaceuticals: Consultancy; Celgene Corp.: Research Funding; La Jolla Pharmaceutical: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Protagonist Therapeutics: Consultancy. Viprakasit:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Agios: Consultancy, Research Funding. Cappellini:Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Vifor: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Kraus:F. Hoffmann-La Roche Ltd: Employment. Cech:F.Hoffmann-La Roche Ltd: Employment. Dietmar:F. Hoffmann-La Roche Ltd: Employment. Winter:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mazer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nave:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Dukart:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Schaedeli Stark:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Koerner:F. Hoffmann-La Roche Ltd: Employment. Khwaja:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Hermosilla:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership.

Author notes

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Asterisk with author names denotes non-ASH members.